Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial.
Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial.
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DOI：
10.1016/s1470-2045(13)70513-8
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发表时间：
2014-01
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影响因子：
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通讯作者：
Byrd JC
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作者：
O'Brien S;Furman RR;Coutre SE;Sharman JP;Burger JA;Blum KA;Grant B;Richards DA;Coleman M;Wierda WG;Jones JA;Zhao W;Heerema NA;Johnson AJ;Izumi R;Hamdy A;Chang BY;Graef T;Clow F;Buggy JJ;James DF;Byrd JC
化学免疫疗法已导致实现疾病应答的患者数量增加，慢性淋巴细胞白血病年轻患者的总生存期延长;然而，其在老年患者中的应用受到大量骨髓抑制和感染的限制。我们的目的是评估伊克替尼（一种口服布鲁顿酪氨酸激酶（BTK）共价抑制剂）在65岁及以上慢性淋巴细胞白血病初治患者中的安全性和活性。在我们的开放标签1b/2期试验中，我们在美国的临床研究中心招募了既往未经治疗的患者。符合条件的患者年龄至少为65岁，患有需要治疗的症状性慢性淋巴细胞白血病或小淋巴细胞淋巴瘤。患者接受28天为一周期的每日一次的依鲁替尼420 mg或依鲁替尼840 mg。在入组开始后，停止840 mg剂量给药，因为已显示剂量的活性相当。主要终点是剂量固定方案在所有接受治疗的患者中不良事件的频率和严重程度方面的安全性。本研究注册于ClinicalTrials.gov，编号NCT 01105247。在2010年5月20日至2012年12月18日期间，我们招募了29例慢性淋巴细胞白血病患者和2例小淋巴细胞淋巴瘤患者。中位年龄为71岁（范围65-84岁），23例（74%）患者至少70岁。毒性主要为轻度至中度（1-2级）。21例（68%）患者发生腹泻（14例[45%]患者为1级，3例[10%]患者为2级，4例[13%]患者为3级）。15例（48%）患者发生恶心（12例[39%]患者为1级，3例[10%]患者为2级）。10例（32%）患者发生疲乏（5例[16%]患者为1级，4例[13%]患者为2级，1例[3%]患者为3级）。3例（10%）患者发生3级感染，但未发生4级或5级感染。1例患者发生3级中性粒细胞减少症，1例发生4级血小板减少症。中位随访22.1个月（IQR 18.4 - 23.2）后，31例患者中有22例（71%）达到客观缓解（95% CI 52.0 - 85.8）; 4例患者（13%）完全缓解，1例患者（3%）结节性部分缓解，17例患者（55%）部分缓解。在老年、既往未接受过治疗的症状性慢性淋巴细胞白血病或小淋巴细胞淋巴瘤患者中，伊曲替尼的安全性和活性令人鼓舞，值得在3期试验中进一步研究。药理学，白血病和淋巴瘤协会，D沃伦布朗基金会，迈克尔托马斯先生和夫人，哈里曼古里安基金会，P50 CA 140158教授J C伯德医学博士。
Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic lymphocytic leukaemia; however, its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic lymphocytic leukaemia. In our open-label phase 1b/2 trial, we enrolled previously untreated patients at clinical sites in the USA. Eligible patients were aged at least 65 years, and had symptomatic chronic lymphocytic leukaemia or small lymphocytic lymphoma requiring therapy. Patients received 28 day cycles of once-daily ibrutinib 420 mg or ibrutinib 840 mg. The 840 mg dose was discontinued after enrolment had begun because comparable activity of the doses has been shown. The primary endpoint was the safety of the dose-fixed regimen in terms of frequency and severity of adverse events for all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01105247. Between May 20, 2010, and Dec 18, 2012, we enrolled 29 patients with chronic lymphocytic leukaemia and two patients with small lymphocytic lymphoma. Median age was 71 years (range 65–84), and 23 (74%) patients were at least 70 years old. Toxicity was mainly of mild-to-moderate severity (grade 1–2). 21 (68%) patients had diarrhoea (grade 1 in 14 [45%] patients, grade 2 in three [10%] patients, and grade 3 in four [13%] patients). 15 (48%) patients developed nausea (grade 1 in 12 [39%] patients and grade 2 in three [10%] patients). Ten (32%) patients developed fatigue (grade 1 in five [16%] patients, grade 2 in four [13%] patients, and grade 3 in one [3%] patient). Three (10%) patients developed grade 3 infections, although no grade 4 or 5 infections occurred. One patient developed grade 3 neutropenia, and one developed grade 4 thrombocytopenia. After a median follow-up of 22·1 months (IQR 18·4–23·2), 22 (71%) of 31 patients achieved an objective response (95% CI 52·0–85·8); four patients (13%) had a complete response, one patient (3%) had a nodular partial response, and 17 (55%) patients had a partial response. The safety and activity of ibrutinib in elderly, previously untreated patients with symptomatic chronic lymphocytic leukaemia, or small lymphocytic lymphoma is encouraging, and merits further investigation in phase 3 trials. Pharmacyclics, Leukemia and Lymphoma Society, D Warren Brown Foundation, Mr and Mrs Michael Thomas, Harry Mangurian Foundation, P50 CA140158 to Prof J C Byrd MD.